The present invention is concerned with a novel process for the preparation of 2-(alkoxyalkylidene)-3-ketoalkanoic acid esters, from 3-ketoalkanoic acid esters. The process is characterized by the condensation of 3-ketoalkanoic acid esters with trialkyl orthoesters catalyzed by a tertiary amine carboxylate salt.
The reaction of orthoesters with active methylene compounds, such as 1,3-diketones, acylacetic esters, malonic esters, malononitriles and nitriloacetic esters in the presence of a catalyst, is a general reaction well known in the art for preparing 2-(alkoxyalkylidene) compounds. See Robert H. DeWolfe, Carboxylic Ortho Acid Derivatives, pp 231–235, Academic Press, New York, 1970. The reaction of triethyl orthoformate with various active methylene compounds in the presence of acetic anhydride has been described. See Claisen, Ber. 26, 2729, (1893), Ann 279, 16, (1897). In the case of diethyl malonate, zinc chloride was also found necessary to catalyze the reaction. Claisen also found that the substitution of acetic acid for acetic anhydride did not prove satisfactory. Other investigators have shown that acetic anhydride reacts first with the orthoester to form a diacetoxyalkoxy compound, which subsequently reacts with the active methylene compound to give the alkoxyalkylidene product. See Post et al, J. Org. Chem. 2, 260 (1937). Further, reactions between orthoesters and active methylene compounds proceed without acetic anhydride. See Jones, J. Am. Chem. Soc., 74, 4889–4891 (1952). U.S. Pat. No. 2,824,121 discloses and claims a process for the reaction of orthoesters with various active methylene compounds catalyzed by acetic acid alone. Also, the reaction of methyl acetoacetate with trimethyl orthoacetate and ethyl acetoacetate with triethyl orthoacetate catalyzed by boron trifluoride etherate has been described. See Emeline et al, Zh. Obshsch. Khim., 133–134, 64 (1994). And, U.S. Pat. No. 4,808,747 discloses the reaction of certain active methylene compounds with aldehydes and ketones, catalyzed by various metal carboxylates.
As compared with the processes known in the art, the process of the present invention produces an isolated product at a higher yield as well as a superior method of purification.
The products of the present invention, 2-(alkoxyalkylidene)-3-ketoalkanoic acid esters such as, for example, those represented by structural Formula 3, are chemical intermediates, useful for the synthesis of various substituted heterocyclic compounds.
Such heterocyclic compounds include, but are not limited to, substituted pyrimidine 5-carboxylic acid esters, substituted pyrimidone carboxylic acid esters, substituted pyrazole carboxylic acid esters, substituted oxazole carboxylic acid esters and substituted 1H-pyrazolo[3,4-b]pyrid-5-ones. These substituted heterocyclic compounds are in turn useful precursors for diverse pharmaceutical, herbicidal and insecticidal agents. In particular, the substituted pyrimidine 5-carboxylic acid esters intermediates are useful precursors to a variety of CCR5 inhibitors such as, for example, those compounds discussed hereafter.
Antagonists of the CCR5 receptor are useful for the treatment of AIDS and related HIV infections. CCR5 receptors have also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
WO 00/66559, published Nov. 9, 2000, and U.S. Pat. No. 6,387,930, incorporated herein by reference, disclose the piperidine compound of Formula A, 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1′-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine, its acid salt (the compound of Formula B) and pharmaceutical compositions comprising formulas A and B:


The compounds of Formulas A and B are antagonists of the CCR5 receptor and are useful for the treatment of AIDS and related HIV infections.
The piperazine compound of Formula C, piperidine, 4-[4-[(1R)-[4-(trifluoromethyl)phenyl]-2-methoxyethyl]-(3S)-methyl-1-piperazinyl]-4-methyl-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl, its acid salt (Formula D), and pharmaceutical compositions comprising the compounds of formulas C and D are disclosed in U.S. Pat. No. 6,391,865. The piperazine compound of Formula C (a free base) and its acid salt shown in Formula D, are disclosed therein as being useful as antagonists of CCR5 receptor.

The inventive process described herein can be used to make 2-(alkoxyalkylidene)-3-ketoalkanoic acid esters, the compounds of Formula 3, which in general can then be used to make substituted pyrimidine 5-carboxylic acid ester intermediates. The substituted pyrimidine 5-carboxylic acid esters can then be converted to the compounds of Formulas A, B, C and D.
In view of the importance of the antagonists of the CCR5 receptor, new methods of making such antagonists including new more efficient and less expensive ways of making precursors and intermediates for the same are always of interest.